Back to EveryPatent.com
United States Patent | 5,756,097 |
Landucci ,   et al. | May 26, 1998 |
This invention relates to processes and compositions for the immunotherapeutic treatment of cancer and non-malignant tumors. More particularly, this invention relates to processes and compositions for enhancing the body's immune response by increasing the cytotoxic activity of cells which mediate antibody dependent cellular cytotoxicity. Cells which are characterized by increased cytotoxic activity, as a result of the process of this invention, are useful in methods and compositions for the treatment of various types of cancer and non-malignant tumors.
Inventors: | Landucci; Gary R. (216 Saybrook Ct., Costa Mesa, CA 92627); Mariani; Toni N. (1924 E. River Terr., Minneapolis, MN 55414) |
Appl. No.: | 237595 |
Filed: | May 2, 1994 |
Current U.S. Class: | 424/155.1; 424/85.1; 424/85.2; 424/85.4; 424/93.71; 424/152.1; 424/172.1; 424/174.1; 435/372.3 |
Intern'l Class: | A61K 045/05; A61K 039/395; A61K 038/20; A61K 038/21 |
Field of Search: | 424/934,85.1,85.2,85.4,85.8,155.1,152.1,93.71,172.1,174.1 435/240.2,372.3 |
3719182 | Mar., 1973 | Rose. | |
3964467 | Jun., 1976 | Rose. | |
4152208 | May., 1979 | Quirgis. | |
4390623 | Jun., 1983 | Fabricius et al. | |
4464355 | Aug., 1984 | Fabricius et al. | |
4596774 | Jun., 1986 | Chang et al. | |
4690915 | Sep., 1987 | Rosenberg. | |
4844893 | Jul., 1989 | Honsik et al. | |
5308626 | May., 1994 | Landucci et al. | 424/155. |
Foreign Patent Documents | |||
2010089 | Jun., 1979 | GB. | |
2106935 | Jan., 1985 | GB. |
Baines, M.G., et al, "Involvement of Transferrin and Transferrin Receptors in Human Natural Killer Effector: Target Interaction," Immunol. Lett., 7:51-55 (1983) ›Immunochem. 99, p. 519, abst. No. 211018u (1983)!. Brunswick, M. and Lake, P., "Obligatory Role of Gamma Interferon in T Cell Replacing Factor-Dependent, Antigen-Specific Murine B Cell Responses," J. Exp. Med., 161:953-971 (1985). Burns, G.F., et al, "In Vitro Generation of Human Activated Lymphocyte Killer Cells: Separate Precursors and Modes of Generation of NK-like Cells and `Anomalous` Killer Cells," J. Immunol., 133(3):1656-1663 (1984). Chang, A.E., et al, "Systemic Administration of Recombinant Human Interleukin-2 in Mice," J. Biol. Response Modifiers, 3(5):561-571 (1984). Cheever, M.A., et al, "Potential for Specific Cancer Therapy with Immune T Lymphocytes," J. Biol. Response Modifiers, 3(2):113-127 (1984). Cohen, B.L., et al., "Suppression by Alpha-Fetoprotein of Murine Natural Killer Cell Activity Stimulated in Vitro and in Vivo by Interferon and Interleukin 2," Scand. J. Immuno., 23:211-223 (1986) ›Immunochem. 104, pp. 533-534, abst. No. 146971e (1986)!. Diener, E., et al, "Specific Immunosuppression by Immunotoxins Containing Daunomycin," Science, 231:148-150 (1986). Engers, H.D., et al, "Functional Activity In Vivo of Effector T Cell Populations II. Anti-Tumor Activity Exhibited B Syngeneic Anti-MoMULV-Specific Cytolytic T Cell Clones," J. Immunol., 133(3):1664-1670 (1984). Fabricius, H.A. and Stahn, R., "Human Primary T-Cell Lines in Lectin-free Media," Immunobiol., 156:364-371 (1979). Fridman, W.H., et al, "Interferon Enhances the Expression of Fe.tau. Receptors," J. Immunol., 124(5):2436-2441 (1980). Fukui, H. and Reynolds, C.W.,"Characterization of Rat Large Granular Lymphocytes in NK and ADCC and Their Modulation by Biological Response Modifiers," Proc. 14th International Congress of Chemotherapy, Kyoto, Japan, Jun. 23-28, 1985. In: Recent Advances in Chemotherapy Anti Cancer Section 2, Ed. Joji Ischigami, University of Tokyo Press: pp. 971-972 (1985). Fujiwara, H., et al, "The Role of Tumor-Specific Lyt-1.sup.+ 2.sup.- T Cells in Eradicating Tumor Cells In Vivo," J. Immunol., 133(3):1671-1676 (1984). Fuson, E.W., et al, "Antibody-Dependent Cell-Mediated Cytotoxicity by Human Lymphocytes," J. Immunol., 120(5):1726-1732 (1978). Gore, M.E., et al, "Antibody-Dependent-Cellular-Cytotoxicity Against Cultured Human Breast Cancer Cells Mediated by Human Effector Cells Using Monoclonal and Polyclonal Antibodies," Br. J. Cancer, 48:877-879 (1983). Greenberg, P.D. and Cheever, M.A., "Treatment of Disseminated Leukemia with Cyclophosphamide and Immune Cells: Tumor Immunity Reflects Long-Term Persistence of Tumor-Specific Donor T Cells," J. Immunol., 133(6):3401-3407 (1984) ›Greenberg, et al I!. Greenberg, P.D., et al, "Therapy of Disseminated Murine Leukemia with Cyclophosphamide and Immune Lyt-1.sup.+ 2.sup.- T Cells," J. Exp. Med., 161:1122-1134 (1985) ›Greenberg, et al II!. Greiner, J.W., "Enhanced Expression of Surface Tumor-associated Antigens on Human Breast and Colon Tumor Cells after Recombinant Human Leukocyte .alpha.-Interferon Treatment," Cancer Res., 44:3208-3214 (1987). Grimm, E.A., et al, "Lymphokine-Activated Killer Cell Phenomenon: Lysis of Natural Killer-resistant Fresh Solid Tumor Cells by Interleukin-2 Activated Autologous Human Peripheral Blood Lymphocytes," J.Exp. Med., 155:1823-1841 (1982). Guyre, P.M., et al, "Recombinant Immune Interferon Increases Immunoglobulin G Fc Receptors on Cultured Human Mononuclear Phagocytes," J. Clin. Invest., 72:393-397 (1983). Hefeneider, S.H., et al, "In Vivo Interleukin 2 Administration Augments the Generation of Alloreactive Cytolytic T Lymphocytes and Resident Natural Killer Cells," J. Immunol., 130(1):222-227 (1983). Imai, K., et al, "Differential Effect of Interferon on the Expression of Tumor-Associated Antigens and Histopcompatibility Antigens on Human Melanoma Cells: Relationship to Susceptibility to Immune Lysis Mediated by Monoclonal Antibodies," J. Immunol., 127(2):505-508 (1981). Imai, K., et al, "ADCC of Cultured Human Melanoma Cells: Analysis with Monoclonal Antibodies to Human Melanoma-associated Antigens," Scand. J. Immunol., 14:369-377 (1981). Issekutz. T.B., "Effects of Six Different Cytokines on Lymphocyte Adherence to Microvascular Endothelium and In Vivo Lymphocyte Migration in the Rat," J. Immunol., 144(6):2140-2146 (1990). Jones, J.F. and Segal, D.M., "Antibody-Dependent Cell-Mediated Cytolysis (ADCC) with Antibody-Coated Effectors: New Methods for Enhancing Antibody Binding and Cytolysis," J. Immunol., 125(2):926-933 (1980). Karpovsky, B., et al, "Production of Target-Specific Effector Cells Using Hetero-Cross-Linked Aggregates Containing Anti-Target Cell and Anti-Fe.tau. Receptor Antibodies," J. Exp. Med., 160:1686-1701 (1984). Kedar, E., et al, "Immunotherapy of Murine and Human Tumors in Mice with Lymphokines and Interleukin-2-Propagated Lymphocytes," J. Biol. Response Modifiers, 3:517-526 (1984). Kimber, I., et al, "Influence of Lectin-Free Interleukin-2 on Natural and Antibody-Dependent Cellular Cytotoxicity," J. Clin. Lab. Immunol., 15:77-84 (1984). Kosugi, A., et al., "Tumor-Specific Immunotherapy: Active Immunotherapy by Augmenting the Induction of Tumor-Specific Effector T Cells through a T-T Cell Interaction Mechanism," Jpn. J. Cancer Chemotherapy, 11(8):1527-1535 (1984). Lanier, L.L, et al, "Recombinant Interleukin 2 Enhanced Natural Killer Cell-Mediated Cytotoxicity in Human Lymphocyte Subpopulations Expressing the Leu 7 and Leu 11 Antigens," J. Immunol., 134(2):794-801 (1985). Lotze, M.T., et al, "Lysis of Fresh and Cultured Autologous Tumor by Human Lymphocytes Cultured in T-Cell Growth Factor," Cancer Res., 41:4420-4425 (1981). Lotze, M.T., et al, "Systemic Administration of Interleukin-2 in Humans," J. Biol. Response Modifiers, 3(5):475-482 (1984). Lowenthal, J.W., et al, "Antigenic Stimulation Regulates the Expression of Il 2 Receptors in a Cytolyitc T Lymphocyte Clone," J. Immunol., 134(2):931-939 (1985). Mazumder, A., et al, "Lysis of Fresh Human Solid Tumors by Autologous Lymphocytes Activated In Vitro with Lectins," Cancer Res.,42:913-918 (1982). Mazumder, A., et al , "Phase I Study of the Adoptive Immunotherapy of Human Cancer with Lectin Activated Autologous Mononuclear Cells," Cancer, 53:896-905 (1984). Merluzzi, V.J. and Last-Barney, K., "Expansion of Murine Cytotoxic Precursors In Vitro and In Vivo by Purified Interleukin-2," J. Biol. Response Modifiers, 3(5):468-474 (1984). Moretta, L., et al, "Surface Markers of Cloned Human T Cells with Various Cytolytic Activities," J. Exp. Med., 154:569-579 (1981). Mule, J.J., et al, "Active Immunotherapy of Established Pulmonary Metastases with LAK Cells and Recombinant Interleukin-2," Science, 225:1487-1489 (1984). Nair, M.P.N. and Schwartz, S.A., "Suppression of Human Natural and Antibody-Dependent Cytotoxicity by Soluble Factors from Unstimulated Normal Lymphocytes," J. Immunol., 129(6):2511-2518 (1982). Nio, Y., et al, "Augmentation of Cytotoxicity of Lymphokine Activated Killer Cells on Ovarian Tumor Cells by Various Biological Response Modifiers," AntiCancer Res., 10:441-446 (1990). Phillips, J.H. and Lanier, L.L., "A Model for the Differentiation of Human Natural Killer Cells: Studies on the In Vitro Activation of Leu-11+ Granular Lymphocytes with a Natural Killer-sensitive Tumor Cell, K 562," J. Exp. Med., 161:1464-1482 (1985). Plate, J.M.D., et al, "Cytokines Involved in the Generation of Cytolytic Effector T Lymphocytes," Ann. N.Y. Acad. Sci., 532, 149-157 (1988). Riccardi, C., et al, "In Vivo Effects of Cytokines in Development of Natural Killer Cells and Antitumor Activity in Lethally Irradiated Bone Marrow Transplanted Recipients," J. Biol. Response Modifiers, 9(1):15-23 (1990). Roder, J.C., et al, "Target-Effector Interaction in the Human and Murine Natural Killer System: Specificity and Xenogeneic Reactivity of the Solubilized Natural Killer-Target Structure Complex and Its Loss in a Somatic Cell Hybrid," J. Exp. Med., 150:471-481 (1979). Rosenberg, S.A. and Terry, W.D., "Passive Immunotherapy of Cancer in Animals and Man," Adv. in Cancer Res., 25:323-388 (1977). Rosenberg, S.A., "Immunotherapy of Cancer by Systemic Administration of Lymphoid Cells Plus Interleukin-2," J.Biol. Response Modifiers, 3:501-511 (1984). Rosenstein, M., et al, "Adoptive Immunotherapy of Established Syngeneic Solid Tumors: Role of T Lymphoid Subpopulations," J. Immunol., 132(4):2117-2122 (1984). Rouse, B.T., et al, "Augmentation of Immunity to Herpes Simplex Virus by In Vivo Administration of Interleukin 2," J. Immunol., 134(2):926-930 (1985). Schulz, G., et al, "Monoclonal Antibody-Directed Effector Cells Selectively Lyse Human Melanoma Cells In Vitro and In Vivo," Proc. Natl. Acad. Sci., 80:5407-5411 (1983). Sears, H.F., et al, "Effects of Monoclonal Antibody Immunotherapy on Patients with Gastrointestinal Adenocarcinoma," J. Biol. Response Modifiers, 3:138-150 (1984). Shaw, A.R.E., et al, "Modulation of Human Natural Killer Cell Activity by Recombinant Human Interleukin 2," Cell Immunol., 91:193-200 (1985). Simone, C.B., "Directed Effector Cells Selectively Lyse Human Tumour Cells," Nature, 297:234-236 (1982). Staerz, U.D., et al, "Hybrid Antibodies Can Target Sites for Attack by T Cells," Nature, 314:628-631 (1985). Torsteinsdottir, S., et al, "Differential Recognition of Tumor-Derived and In Vitro Epstein-Barr Virus-Transformed B-Cell Lines by Fetal Calf Serum-Specific T4-Positive Cytotoxic T-Lymphocyte Clones," Cell. Immunol., 98(2):453-466 (1986). Walker, E.B., et al, "Murine Gamma Interferon Activates the Release of a Macrophage-Derived Ia-inducing Factor that Transfers Ia Inductive Capacity," J. Exp. Med., 159:1532-1547 (1984). Wallach, D., et al, "Preferential Effect of .tau. Interferon on the Synthesis of HLA Antigens and their mRNAs in Human Cells," Nature, 299:833-836 (1982). Werkmeister J.A., et al, "Identification of a Structure on Human Melanoma Cells Recognized by CTL Exhibiting Anomolous Killer Cell Function," J. Immunol., 135(1):689-695 (1985). Yamasaki, T., "A New Experimental Approach to the Specific Adoptive Immunotherapy for Malignant Gliomas," Arch. Japan Chir., 52(6):783-801 (1983) ›Chem. Abst., 101, p. 474, abst. No. 21899u (1984)!. Yeh, N.H., et al, "Interferon Alpha Synthesis by Human Thymocytes and the Immunoregulatory Functions of Natural and Recombinant Alpha Interferons," Chem. Abstr., 103, p. 562, abst. No. 140032g (1985). |
TABLE I ______________________________________ Effector: Target % Specific % Inhibition of Assay # Ratio cytotoxicity proliferation ______________________________________ 1 100 51.7 107.4 50 38.5 89.4 25 30.4 59.2 12.5 28.1 33.3 6.25 18.4 25.0 2 100 73.7 99.7 50 39.1 99.8 25 29.6 91.9 12.5 -- 55.7 6.25 -- 34.9 3 100 61.5 84.2 50 53.0 69.4 25 41.2 46.1 12.5 18.6 32.3 6.5 6.7 24.0 ______________________________________
TABLE II ______________________________________ % Specific % Inhibition Target Antibody cytotoxicity rocked not-rocked ______________________________________ Zbtu none 6.1 0 0 GAGPA 79.5 86.5 88.1 Nalm-6 none 3.4 0 0 RaNalm 58.9 103.5 93.8 CALLA 7.1 47.3 10.9 ______________________________________
TABLE III ______________________________________ % Viability % Cytotoxicity % Viable Cells Donor Day 0 Day (X) Day 0 Day (X) Recovered ______________________________________ 1 94 93 (12) 76 68 (12) 67 2 92 80 (34) 71 49 (34) 58 3 97 94 (58) 71 58 (58) 62 ______________________________________
TABLE IV ______________________________________ Percent Specific ADCC - Day 5 MLC Effector:Target Ratio Unprimed Primed ______________________________________ 140:1 19.9 56.0 47:1 10.4 47.0 16:1 8.3 31.2 ______________________________________
TABLE V ______________________________________ Percent Survival of Treated Tumor-Bearing Mice Group 6 weeks 10 weeks 18 weeks ______________________________________ A 20 0 0 B 10 0 0 C 100 90 40 ______________________________________
TABLE VI ______________________________________ % Specific ADCC Stimulator Day 0 Day 3 Day 5 Day 7 ______________________________________ Allogeneic 38.1 61.5 86.2 79.5 Xenogeneic 38.1 53.2 66.6 59.7 ______________________________________
TABLE VII ______________________________________ % Specific ADCC Units 4.degree. C. 37.degree. C. IFN Day 0 Day 1 Day 2 Day 4 Day 1 Day 2 Day 4 ______________________________________ 100 36.3 39.1 43.7 45.9 42.8 46.6 39.1 200 36.3 ND ND ND 49.7 51.9 59.3 600 36.3 43.8 51.1 49.6 36.4 53.6 51.2 1000 36.3 33.2 36.1 39.4 ND ND ND ______________________________________ % specific ADCC are mean values ND = Not determined.
TABLE VIII ______________________________________ % Specific ADCC Units 4.degree. C. 37.degree. C. IL-2 Day 0 Day 1 Day 2 Day 4 Day 1 Day 2 Day 4 ______________________________________ 30 43.2 36.9 46.3 51.2 51.6 62.3 55.4 50 43.2 ND ND ND 39.5 51.9 60.7 100 43.2 48.7 49.6 54.6 ND ND ND 250 43.2 39.2 55.4 49.3 56.4 62.1 57.8 500 43.2 ND ND ND 60.6 63.7 59.4 750 43.2 36.1 52.7 61.1 61.4 60.9 58.3 ______________________________________ % specific ADCC are mean values ND = Not determined.
TABLE IX ______________________________________ % Specific ADCC Rabbit anti-Nalm-6 labelled Nalm-6 GAGPA-labelled Zbtu targets targets Group Day 0 Day 2 Day 4 Day 6 Day 0 Day 4 ______________________________________ A 41.4 66.7 89.1 76.3 36.3 75.2 B 41.4 ND 79.8 73.6 36.3 88.7 C 41.4 90.1 106.5 101.3 36.3 94.3 D 41.4 88.2 91.4 ND 36.3 ND E 41.4 75.5 86.3 89.1 36.3 ND ______________________________________ A 600 units IFN, 500 units IL2 B 600 units IFN, 250 units IL2 C 200 units IFN, 600 units IL2 D 600 units IFN, 600 units IL2 E 1000 units IFN, 100 units IL2
TABLE X ______________________________________ % Specific ADCC 4.degree. C. 37.degree. C. Culture Day Day Day Day Day Day Day Medium 0 1 2 4 1 2 4 ______________________________________ A 38.6 39.6 41.3 38.6 39.3 40.2 42.8 B 38.6 43.1 36.3 31.8 41.4 33.2 36.8 C 38.6 68.7 83.2 79.4 81.5 93.1 86.4 D 38.6 64.4 69.7 91.5 86.7 78.5 85.3 ______________________________________
TABLE XI ______________________________________ % Specific ADCC Anti-CALLA Rabbit anti-Nalm-6 labelled Nalm-6 labelled Nalm-6 Culture targets (37.degree. C.) targets (37.degree. C.) Medium Day 0 Day 2 Day 0 Day 2 ______________________________________ A 12.1 17.3 32.1 31.1 B 12.1 13.4 32.1 39.5 C 12.1 37.8 32.1 69.4 D 12.1 39.1 32.1 61.6 ______________________________________ A RPMI1640 supplemented with 1% Ultroser G (LBK Industries, Gaithersburg Maryland) B RPMI1640 supplemented with 5% autologous serum C RPMI1640 supplemented with heat inactivated 5% fetal calf serum (Gibco Laboratories, Grand Island, New York) D RPMI1640 supplemented with 5% pooled allogenic serum
TABLE XII ______________________________________ % Anti-Proliferation Zbtu targets Nalm-6 targets Effector Day 1 Day 2 Day 1 Day 2 ______________________________________ Non-activated 24.3 32.1 20.1 19.6 Activated 84.2 78.8 82.6 92.3 ______________________________________
TABLE XIII ______________________________________ Target % Specific % Inhibition cell Antibody Effector cytotoxicity proliferation ______________________________________ Zbtu None unarmed 5.9 0 Zbtu GAGPA unarmed 79.1 86.6 Zbtu GAGPA armed 65.3 79.7 Zbtu THY 1.2(2a) unarmed 78.6 104.5 Zbtu THY 1.2(2a) armed 74.3 88.8 Zbtu THY 1.2(2b) unarmed 82.5 86.3 Zbtu THY 1.2(2b) armed 75.4 89.8 ______________________________________
TABLE XIV ______________________________________ % Specific ADCC Zbtu Autologous targets tumor targets Diag- Treat- Day Day Day Day Patient # nosis ment Status 0 2 0 2 ______________________________________ 1 ALL CC Acute 32.6 58.4 31.1 53.4 2 CML CC Relapse 14.0 21.1 13.3 37.7 3 CLL CC Rem 49.5 83.4 ND ND 4 ALL CC Rem 19.8 62.7 ND ND 5 CLL CC Relapse 8.7 12.2 5.4 18.7 6 CML BMT Rem 31.4 60.9 ND ND 7 T lymph CC Rem 23.2 71.1 ND ND 8 CLL CC Rem 45.1 52.4 ND ND ______________________________________ Definitions: ALL acute lymphocytic leukemia CLL chronic lymphocytic leukemia CML chronic myelogenous leukemia T lymph "T" cell lymphoma CC combined chemotherapy BMT bone marrow transplant (allogeneic) Rem remission ND not determined.
TABLE XV ______________________________________ Patient Diag- Treat Antibody THY 1.2: # nosis ment Status None GAGPA (2a) (2b) ______________________________________ 1 CML CC Rem 0 16 39 13 2 ALL CC Rem 0 68 71 64 3 CML None Chronic 1 22 45 16 4 CML None Chronic 1 39 65 23 ______________________________________
TABLE XVI ______________________________________ Patient Diag- Treat- Day IFN/ # nosis ment Status 0 FCS IL-2 IFN IL-2 ______________________________________ 1 ALL None Acute 23 -- -- 30 31 2 CML None Chronic 39 45 45 -- -- 3 CML CC Rem 16 40 28 -- -- 4 CML CC Relapse 12 33 20 -- 21 5 CML None Chronic 22 51 -- -- -- ______________________________________
TABLE XVII __________________________________________________________________________ Day 0 Day 1 Day 2 Mean Mean Mean Channel % Positive Channel % Positive Channel % Positive Effector Difference Cells % ADCC Difference Cells % ADCC Difference Cells % ADCC __________________________________________________________________________ Control (4.degree. C.) 62.2 16.9 26.4 64.2 18.1 22.8 60.6 17.2 ND Control (37.degree. C.) 58.6 18.1 31.4 52.9 21.9 27.5 56.9 20.7 30.7 FCS (37.degree. C.) ND ND ND 77.6 34.9 59.8 91.1 31.6 56.3 IFN (37.degree. C.) ND ND ND 76.8 24.2 49.1 77.2 26.3 ND IL-2 (37.degree. C.) ND ND ND 88.2 20.4 52.6 110.2 24.4 61.5 IFN + IL-2 (37.degree. C.) ND ND ND 85.0 37.7 61.4 73.8 34.8 60.9 __________________________________________________________________________ Control RPMI1640 supplemented with 5% autologous serum FCS RPMI1640 supplemented with 5% heat inactivated fetal calf serum IFN RPMI1640 containing 600 units IFN/10.sup.6 cells IL2 RPMI1640 containing 500 units IL2/10.sup.6 cells IFN + IL2 RPMI1640 containing 200 units IFN + 600 units IL2/10.sup.6 cells ND -- Not determined